Fibroblast growth factors (FGFs) and their receptors (FGFRs) are a highly conserved group of proteins with instrumental roles in angiogenesis, vasculogenesis, and wound healing, as well as in tissue patterning and limb formation in embryonic development. FGFs and FGFRs affect cell migration, proliferation, and survival, providing wide-ranging impacts on health and disease.
The FGFR family comprises four major types of receptors, FGFR1, FGFR2, FGFR3, and FGFR4. These receptors are transmembrane proteins having an extracellular domain (ECD), a transmembrane domain, and an intracytoplasmic tyrosine kinase domain. Each of the extracellular domains contains either two or three immunoglobulin (Ig) domains. When there are three Ig domains, they are referred to as D1, D2, and D3. Receptors having two Ig domains typically lack D1. An acidic motif, called the acid box, is located in the linker region between D1 and D2 in the FGFR extracellular domain. The D2 domain of FGFRs contains a heparin binding site. FGFR4 also contains a heparin binding site in D1. The acid box is believed to interact with the heparin binding site in the D2 domain. Furthermore, it has been shown that the FGFR1 and FGFR3 D1 domains are capable of interacting with the D2 and D3 domains. It has been hypothesized that the FGFR1 acid box-mediated interactions with the D2 domain, and the FGFR1 D1 domain-mediated interactions with the D2 and D3 domains play an autoinhibitory role that prevents receptor oligomerization in the absence of FGF ligand. Finally, extracellular FGFR activation by FGF ligand binding to an FGFR initiates a cascade of signaling events inside the cell, beginning with oligomerization of the receptor and activation of receptor tyrosine kinase activity.
To date, there are 22 known FGFs, each with the capacity to bind one or more FGFRs. See, e.g., Zhang et al., J. Biol. Chem. 281:15, 694-15,700 (2006). Several FGFs can bind to and activate each of one or more FGFRs, often with large differences in their affinities for the different FGFRs. Heparin sulfate proteoglycan (“heparin”) is required for the binding of FGFs to FGFRs under certain circumstances. See, e.g., Ornitz et al., Mol. Cell Biol. 12:240 (1992). For example, the mitogenic response to FGF2 (also known as basic FGF (bFGF)) mediated by FGFR1 has been shown to depend on the presence of heparin. See, e.g., Ornitz et al., Mol. Cell Biol. 12:240 (1992).